Melanoma cells treated with GGTI and IFN-gamma allow murine vaccination and enhance cytotoxic response against human melanoma cells

PLoS One. 2010 Feb 3;5(2):e9043. doi: 10.1371/journal.pone.0009043.

Abstract

Background: Suboptimal activation of T lymphocytes by melanoma cells is often due to the defective expression of class I major histocompatibility antigens (MHC-I) and costimulatory molecules. We have previously shown that geranylgeranyl transferase inhibition (done with GGTI-298) stimulates anti-melanoma immune response through MHC-I and costimulatory molecule expression in the B16F10 murine model [1].

Methodology/principal findings: In this study, it is shown that vaccination with mIFN-gand GGTI-298 pretreated B16F10 cells induces a protection against untreated tumor growth and pulmonary metastases implantation. Furthermore, using a human melanoma model (LB1319-MEL), we demonstrated that in vitro treatment with hIFN-gamma and GGTI-298 led to the up regulation of MHC-I and a costimulatory molecule CD86 and down regulation of an inhibitory molecule PD-1L. Co-culture experiments with peripheral blood mononuclear cells (PBMC) revealed that modifications induced by hIFN-gamma and GGTI-298 on the selected melanoma cells, enables the stimulation of lymphocytes from HLA compatible healthy donors. Indeed, as compared with untreated melanoma cells, pretreatment with hIFN-gamma and GGTI-298 together rendered the melanoma cells more efficient at inducing the: i) activation of CD8 T lymphocytes (CD8+/CD69+); ii) proliferation of tumor-specific CD8 T cells (MelanA-MART1/TCR+); iii) secretion of hIFN-gamma; and iv) anti-melanoma specific cytotoxic cells.

Conclusions/significance: These data indicate that pharmacological treatment of melanoma cell lines with IFN-gamma and GGTI-298 stimulates their immunogenicity and could be a novel approach to produce tumor cells suitable for vaccination and for stimulation of anti-melanoma effector cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • B7-2 Antigen / immunology
  • B7-2 Antigen / metabolism
  • Benzamides / pharmacology*
  • Blotting, Western
  • Cell Line, Tumor
  • Coculture Techniques
  • Cytokines / metabolism
  • Cytotoxicity, Immunologic / immunology*
  • Female
  • Flow Cytometry
  • Histocompatibility Antigens Class I / immunology
  • Histocompatibility Antigens Class I / metabolism
  • Humans
  • Interferon-gamma / pharmacology*
  • Jurkat Cells
  • Leukocytes, Mononuclear / cytology
  • Leukocytes, Mononuclear / immunology
  • Leukocytes, Mononuclear / metabolism
  • Melanoma / immunology
  • Melanoma / metabolism
  • Melanoma / pathology
  • Melanoma, Experimental / immunology*
  • Melanoma, Experimental / pathology
  • Mice
  • Mice, Inbred C57BL
  • T-Lymphocytes / immunology
  • T-Lymphocytes / metabolism
  • Up-Regulation / drug effects
  • Vaccination / methods*

Substances

  • B7-2 Antigen
  • Benzamides
  • Cytokines
  • GGTI 298
  • Histocompatibility Antigens Class I
  • Interferon-gamma